Substantial evidence supports the possibility that different neural mechanisms may underlie nerve injury- induced tactile and thermal hypersensitivity. Our recent preliminary data, for example, show that nerve-injury induced thermal hypersensitivity resolves at approximately 45 days post-injury, while tactile hypersensitivity persists apparently indefinitely (i.e., for at least more than 200 days). Lesions of the dorsal columns (DC) or microinjection of lidocaine into the n. gracilis on the side ipsilateral to the nerve-injury block nerve-injury induced tactile, but not thermal, hypersensitivity, supporting the possibility that tactile hyperresponsiveness may be mediated by large, myelinated fibers. In the absence of nerve injury, cells in the dorsal root ganglion (DRG) and in the n. gracilis either do not express neuropeptide Y (NPY), or express the peptide at very low levels. Following nerve injury, however, NPY -ir is markedly upregulated particularly in medium and large diameter DRG cells. Increased NPY -ir is also seen in the n. gracilis, as well as in the spinal dorsal horn. We propose testing the hypothesis that sustained nerve-injury induced tactile hypersensitivity results from the actions of upregulated NPY in afferent fibers which project to n. gracilis. Our preliminary data show that (a) nerve-injury induced upregulation of NPY -ir occurs in DRG cells and in projections to the ipsilateral n. gracilis through the DC, (b) NPY microinjected into the n. gracilis of uninjured animals produces ipsilateral tactile, but not thermal, hypersensitivity, (c) anti-NPY antiserum given into the n. gracilis ipsilateral to the side of nerve-injury reverses tactile, but not thermal, hypersensitivity and (d) microinjection of either of two NPY receptor antagonists into the n. gracilis ipsilateral to the side of nerve injury reverses tactile, but not thermal, hypersensitivity. Our hypothesis will be tested in Aim I by characterizing the time-course of NPY expression and determining if such expression and activity is consistent with early and/or late aspects of tactile hypersensitivity. Aim 2 will evaluate whether blockade of DC pathways or NPY expression can prevent the development of, or reverse existing, experimental neuropathic pain. Aim 3 will characterize the expression of NPY receptors in the DRG and in n. gracilis before and after nerve injury. Aim 4 will determine the possible contribution of post-synaptic dorsal column cells which project to n. gracilis to nerve injury- induced tactile hypersensitivity by determining if they receive inputs from NPY expressing fibers, and if they express NPY -ir and/or NPY receptors. Understanding the neural mechanisms underlying tactile hypersensitivity is highly significant as tactile allodynia in humans is the most devastating and difficult to manage symptom of clinical neuropathic pain. Selective reversal of injury-induced tactile hypersensitivity by NPY antagonists would have significant implications for treatment of the neuropathic condition.